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Table 1 Clinical DMOAD trials in knee osteoarthritis (placebo-controlled, peer-reviewed and published since 1999)

From: On the predictive utility of animal models of osteoarthritis

Trial

Target

Disease modification

Symptomatic outcome (secondary endpoint)

Preclinical validation in OA model

Structural outcome

Symptomatic outcome

Oral salmon calcitonin (n = 1,176 and n = 1,030; 2 years) [145]

SCB

JSW: no effect. No statistically significant effect on biochemical markers of bone (CTX-I) and cartilage degradation (CTX-II)

WOMAC: no statistically significant effect

Rat MNX and MNX/OVX [146]: 8 weeks, treatment at start

Joint protection, serum CTX-II ↓

NA

    

Dog ACLT: Rx at surgery, 84 days (nasal delivery) [147]

Joint protection (no effect on osteophytes)

NA

    

DMM in mice overexpressing salmon calcitonin [148]

OARSI score ↓

7 weeks after DMM

NA

Intra-articular rFGF18 (n = 168; 12 months) [149]

Cartilage (anabolic)

Primary endpoint, (reduction of cartilage loss in the central medial femorotibial compartment on MRI) not met. Secondary structural endpoints were met

WOMAC: improved

Rat MMT: 6 weeks; Rx start week 3 [150]

Increased thickness of the articular surface of the medial tibial plateau. Reduced degeneration scores

NA

Strontium ranelate (n = 1,371; 3 years) [151]

SCB

JSW: fewer radiographic progressors (both low and high dose)

Beneficial effects on symptoms (high dose only)

Dog ACLT [152]: 16 weeks; Rx start week 4

Cartilage lesions ↓ (macrosc/histol), SCB thickening ↓ (histomorphometry), serum CTXII ↓

NA

    

Rat MMT [153]: 3 or 6 weeks; Rx start at surgery

Cartilage degeneration ↓, SCB remodeling ↓

NA

SD6010, oral selective iNOS inhibitor (n = 1,048; 2 years) [154]

Cartilage

JSW: no effect

No effect on pain or function

Dog ACLT [155, 156]: 10 or 12 weeks; Rx start at surgery

Cartilage lesions ↓ (macrosc/histol), osteophytes ↓, synovial inflammation ↓

NA

    

Collagenase induced arthritis in Nos2 null mice [157]

Cartilage proteoglycan loss ↓, cartilage lesions ↓, osteophytes ↓

NA

    

Rat MMT model [158]

NA

Reversal of mechanical allodynia and reversal of WBD 3 hours after drug administration

Zoledronic acid (n = 59; single infusion; 6 and12 month follow-up) [77]

SCB

MRI BML area: reduction in total BML area significant at 6 but not 12 months

VAS pain scores ↓ at 6 months, but not KOOS

Rat MIA [92], rat MMT [70]

  
    

a) prophylactic

Joint preservation

Reversal of WBD

    

b) therapeutic (early or late intervention)

Partial preservation, diminishes with late intervention

Partial effect, diminishing with late intervention

Vitamin D3 (n = 146; 2 years) [159]

SCB cartilage

MRI cartilage volume: no effect

WOMAC: no effect

Rat pMNX [160]: prophylactic; 40 days

Inconclusive

NA

    

Osteochondrosis/OA in pigs; Vit D3 in diet [161]

No effect on OA incidence or severity of OA lesions, or cartilage biochemistry

NA

Licofelone (5-LOX and COX inhibitor; n = 355; 2 years; not placebo controlled but compared with NSAID) [162]

Inflammation

JSW: no effect

WOMAC: pain improved

Dog ACLT [163]: 12 weeks; Rx start week 4

MRI cartilage volume ↑, cartilage damage and osteophytes ↓(macroscopic evaluation only)

NA

Risedronate

SCB

  

DH guinea pig [164]: up to 24 weeks

OARSI score: no effect. Serum CTX-II ↓

NA

    

NZW rabbits ACLT [165]: 11 weeks; Rx start week 3

Loss of cartilage ↓, SCB damage ↓, serum CTX-II ↓

NA

N = 284 (1 year) [166]

 

JSW: trend toward improvement. Cartilage degradation and bone resorption markers ↓

WOMAC ↓

   

N = 2,483 (2 years) [167]

 

JSW: no effect. uCTXII ↓

WOMAC : no effect

   

N =1,232 (2 years) [168]

 

Preserved SCB integrity

NA

   

Broad-spectrum MMP inhibitor (n =401; 1 year) [169]

Cartilage

JSW: no effect

No effect on pain

rat MIA [170]: 3 weeks; Rx during first week

Cartilage damage ↓

NA

    

STR/Ort mice [171]: 12 weeks

Improved radiographic score and less cartilage and bone damage

NA

Doxycycline (n = 403; 30 months) [172]

Cartilage

JSW: slowed JSN in ipsilateral knee

No effect on pain

Dog ACLT (after dorsal root ganglionectomy) [173]: 8 weeks; Rx at start

Less damage on femoral condyle. No effect on tibial plateau or osteophytes

NA

    

DH guinea pig [174]: 9 months old; 66 days

Less cartilage volume loss (MRI)

NA

    

DMM (mouse) [175]: 4 weeks; Rx at start

Less cartilage loss

NA

  1. ACLT, anterior cruciate ligament transection; BML, bone marrow lesion; COX, cyclo-oxygenase; CTX, C-terminal crosslinked telopeptide type II collagen; DH, Dunkin-Hartley; DMM, destabilization of the medial meniscus; DMOAD, disease-modifying osteoarthritis drug; iNOS, inducible nitric oxide synthase; JSN, joint space narrowing; JSW, joint space width; LOX, lipoxygenase; KOOS, knee injury and osteoarthritis outcome score; MIA, mono-iodoacetate; MMP, matrix metalloproteinase; MMT, medial meniscal tear; MNX, meniscectomy; MRI, magnetic resonance imaging; NA, not applicable; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; OARSI, Osteoarthritis Research Society International; OVX, ovariectomy; Rx, treatment; SCB, subchondral bone; VAS, visual analog score; WBD, weight bearing deficit; WOMAC, Western Ontario and McMaster Osteoarthritis Index